Discovery and Evaluation of a Series of 3-Acylindole Imidazopyridine Platelet-Activating Factor Antagonists

Citations Over TimeTop 12% of 1998 papers

Abstract

Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.

Related Papers

• → Design and Synthesis of Novel Indole β-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors(2004)122 cited
• → Novel selective PPARδ agonists: Optimization of activity by modification of alkynylallylic moiety(2007)10 cited
• → SAR study of the indole moiety of CI-988, a potent and selective CCK-B antagonist(1997)6 cited
• → A Novel Class of Platelet Activating Factor(PAF) Antagonists. II. Modification of the 2-Position of the Glycerol Backbone of PAF-Sulfonamide Isosteres.(1992)3 cited
• → Synthesis and biological activity of the platelet-activating factor antagonist (±)-trans-2-(3-methoxy-4-phenylsulfonylethoxy-5-n-propylsulfonylphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-671,284) and its analogs(1992)6 cited